ABSTRACT This study investigated whether anxiety characteristics independently predicted the onset of myocardial infarction (MI) over an average of 12.4 years and whether this relationship was independent of other psychologic variables and risk factors.
Although several psychosocial factors have been associated with risk for MI, anxiety has not been examined extensively. Earlier studies also rarely addressed whether the association between a psychologic variable and MI was specific and independent of other psychosocial correlates.
Participants were 735 older men (mean age 60 years) without a history of coronary disease or diabetes at baseline from the Normative Aging Study. Anxiety characteristics were assessed with 4 scales (psychasthenia, social introversion, phobia, and manifest anxiety) and an overall anxiety factor derived from these scales.
Anxiety characteristics independently and prospectively predicted MI incidence after controlling for age, education, marital status, fasting glucose, body mass index, high-density lipoprotein cholesterol, and systolic blood pressure in proportional hazards models. The adjusted relative risk (95% confidence interval [CI]) of MI associated with each standard deviation increase in anxiety variable was 1.37 (95% CI 1.12 to 1.68) for psychasthenia, 1.31 (95% CI 1.05 to 1.63) for social introversion, 1.36 (95% CI 1.10 to 1.68) for phobia, 1.42 (95% CI 1.14 to 1.76) for manifest anxiety, and 1.43 (95% CI 1.17 to 1.75) for overall anxiety. These relationships remained significant after further adjusting for health behaviors (drinking, smoking, and caloric intake), medications for hypertension, high cholesterol, and diabetes during follow-up and additional psychologic variables (depression, type A behavior, hostility, anger, and negative emotion).
Anxiety-prone dispositions appear to be a robust and independent risk factor of MI among older men.

[Show abstract][Hide abstract]ABSTRACT: Objective: Anti-anxiety medication in patients with anxiety may lessen the stress and thereby lower their risk for myocardial infarction (MI). The aim of current study is to examine an association between the use of anti-anxiety medication and long-term mortality risk in patients following MI. Methods: A universal national health insurance (NHI) program has been implemented in Taiwan since 1995. We used system sampling database from 1997 to 2008 with a total of 1,000,000 subjects. We included subjects with first episode of MI and were above 30 years old. Sudden death, cardiovascular mortality, and heart failure hospitalization were assessed in all included subjects. Anti-anxiety as well as other medications and risk factors were obtained. Cox regression analysis was used to evaluate the adjusted hazard ratio (HR) for all patients and subgroups. Results: The adjusted HRs of sudden death were significantly associated with increased benzodiazepam (BZD) dosage (HRs = 0.639, 1.003, 1.957 from Q2 to Q4 vs. Q1, p = .019 for trend) during approximately 4.8 years. For cardiac mortality and heart failure hospitalization, there was a J-curve dose-response relationship. The HRs for cardiac mortality were 0.255 (p < .001) and 0.385 (p < .001) for Q2 and Q3 vs. Q1, respectively. For patients receiving higher doses of daily BZDs (> 5 mg), protective effects for cardiac mortality and heart failure hospitalization decreased and a J-curve doseeresponse relationship was seen. Conclusion: Anti-anxiety medications are independent associated with a decreased risk of cardiac mortality and heart failure hospitalization in patients after a new MI.

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FactorsInfarction in Men: The Unique Contribution of Anxiety Among Psychologic Anxiety Characteristics Independently and Prospectively Predict MyocardialThis information is current as of April 17, 2009 http://content.onlinejacc.org/cgi/content/full/51/2/113located on the World Wide Web at: The online version of this article, along with updated information and services, is by on April 17, 2009 content.onlinejacc.orgDownloaded from

Anxiety and depression areamong the most prevalent emo-tional disturbances. Althoughdepression has been well recog-nized as a risk factor for CAD,few studies have scrutinized therole of anxiety. Kawachi et al.(12) reported that a short phobicanxiety measure predicted non-fatal myocardial infarction (MI)and fatal CAD over 2 years inmen. Another study demon-strated that a 5-item anxiety scalepredicted sudden cardiac deathbut not nonfatal CAD over 32years (13). High levels of worry were associated withnonfatal MI and fatal CAD over 20 years (3). Amongcardiac patients, type D personality, jointly defined by socialinhibition and negative affectivity, has been found to predictpoor prognosis (14). In a cross-sectional study with arepresentative sample of the U.S. population, generalizedanxiety disorder, independent of depression, was linked to arisk index of CAD composed of obesity, smoking, and useof medication for hypertension, hypercholesterolemia, anddiabetes (15). In contrast, some studies failed to demon-strate an independent association between anxiety and CAD(16,17).Some common limitations have been noted in thesestudies. First, researchers either used a brief screening tool(12), examined a circumscribed aspect of anxiety (3), orprovided insufficient information for the anxiety measure(16). Furthermore, earlier studies rarely considered theoverlap between anxiety and other coronary-prone psycho-logic factors (e.g., depression, anger, or hostility), thusfailing to discern whether anxiety presented a unique risk forCAD. Kubzanksy et al. (18) attempted to address this issueand found that although anger, anxiety, and general distresswere associated with CAD individually, only anxiety andgeneral distress were significant when considered simulta-neously. That study did not, however, include severalprominent characteristics, such as hostility and type Abehavior. It remains unclear whether the observed effectswere independent of these psychologic correlates.The present study addresses the issues raised above. First,using an established and comprehensive psychologic instru-ment, we examined whether anxiety independently andprospectively conferred higher risk for MI while controllingfor major sociodemographic and biomedical risk factors.Second, we tested whether the anxiety-MI association couldbe explained by other psychologic risk factors observed inearlier studies, including depression, hostility, type A be-havior, anger, and negative emotion. In addition, we ex-plored whether sociodemographic background, biomedicalrisk factors, health behaviors, and use of medications forcardiovascular risk factors during follow-up mediated ormoderated the effect of anxiety on MI onset.MethodsParticipants. The NAS (Normative Aging Study) is alongitudinal study investigating the biomedical and psycho-social changes associated with aging among a group ofinitially healthy men in the Boston area. Its sampling anddesign have been reported in detail (19). Participants in thepresent study were required to: 1) have completed theMinnesota Multiphasic Personality Inventory (MMPI) in1986; 2) have received a physical examination with bloodassays near the time of MMPI administration; and 3) bewithout a history of CAD (angina pectoris, ischemic heartdisease, and MI) and diabetes at the baseline. All partici-pants provided written informed consent for the study.Procedure of medical examination. After 1986, all partic-ipants received medical examinations every 3 years. Duringexaminations, the physician updated participants’ medicalhistories and reviewed hospital records for possible CADevents. The research team obtained participants’ vital signs,anthropometric measures, and fasting blood samples forlaboratory assays. Participants also completed question-naires assessing sociodemographic background and healthbehaviors, including caloric intake, smoking, and alcoholconsumption. In 1986, active participants received a com-prehensive psychosocial assessment, including the MMPIForm AX, from which psychologic measures were derived.Anxiety measures. Four anxiety scales from the MMPI(20) and an overall anxiety factor derived from these scaleswere examined. The MMPI is a comprehensive assessmentof enduring personality patterns reflecting an individual’scognitive, affective, and behavioral tendencies (21). These 4scales assess characteristics that give rise to thoughts, feel-ings, and behaviors indicative of anxiety tendencies. Indi-viduals endorsing these characteristics are more likely toexhibit anxiety symptoms or develop anxiety disorders.PSYCHASTHENIA. Psychasthenia is an MMPI basic scalewith 40 true-false items that assess excessive doubts, obses-sive ruminations, and irrational compulsions (22). Its test-retest reliability ranges from 0.74 to 0.93 (23). Its validityhas been evidenced by its wide use in research and highassociations with other anxiety scales (23).SOCIAL INTROVERSION. Social introversion is an MMPIbasic scale with 26 true-false items tapping anxiety, insecu-rity, and discomfort during interpersonal and social situ-ations (20). Its test-retest reliability ranges from 0.80 to0.96 (23). Its validity has been demonstrated by itsassociations with other measures of social anxiety (23)and prediction of behavioral responses to anxiety-inducing chemical agents (24).PHOBIA. Phobia was assessed with the 27-item Phobia scalefrom the MMPI Wiggins content scales (25). High scoressuggest excessive anxiety and fears of specific animals,situations, or objects. It has been reported as one of the mosteffective MMPI anxiety measures in clinical applications(26). It demonstrates high convergent validity with other by on April 17, 2009 content.onlinejacc.orgAbbreviationsand AcronymsBMI ? body mass indexCAD ? coronary arterydiseaseHDL-C ? high-densitylipoprotein cholesterolLDL-C ? low-densitylipoprotein cholesterolMI ? myocardial infarctionRR ? relative riskSBP ? systolic bloodpressure114Shen et al.Anxiety and Myocardial InfarctionJACC Vol. 51, No. 2, 2008January 15, 2008:113–9Downloaded from

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anxiety measures and utility in identifying individuals whoare fearful, phobic, and worrisome (27).MANIFEST ANXIETY. The 50-item Manifest Anxiety scaleassesses a predisposition to experience tension and somaticsymptoms of anxiety in stressful situations. Its test-retestreliability ranges from 0.81 to 0.89 (28) and internalconsistency around 0.92 (29). Its validity is evidenced by itsassociations with other anxiety measures, physiologic man-ifestations of anxiety, and effects on test performance (29).OVERALL ANXIETY FACTOR. To compute an index for over-all anxiety, we conducted a principal components analysisand extracted a single factor that explained 70% of the totalvariance with factor loadings of 0.92, 0.77, 0.73, and 0.92on psychasthenia, social introversion, phobia, and manifestanxiety, respectively. The factor scores of overall anxietywere calculated to represent a summary anxiety index inanalyses.CLINICALLY SIGNIFICANT ANXIETY. To identify individualswith excessively elevated anxiety on these measures, wedefined clinical levels of anxiety, by convention, as T scores?65 (30).Other psychosocial measures. TYPE A BEHAVIOR. The19-item MMPI-2 Type A scale assesses time urgency,competitiveness, and hostile tendency. Individuals withhigh scores are hard-driving, fast-pacing, impatient, irrita-ble, and short-tempered. This scale has been associated withCAD onset in a previous study (5).HOSTILITY. The Cook-Medley Hostility Scale measures aperson’s hostile affects, cynical attitudes, and antagonisticresponding style (31). Individuals with high scores are likelyto interpret their environment as threatening and others asharboring harmful intent. It has been shown to predictCAD onset in past studies (6).ANGER. Anger was measured with the 16-item MMPI-2Anger scale, tapping excessive anger expression and inabilityto control anger (32). Individuals with higher scores arehot-headed, grouchy, and likely to be verbally or physicallyaggressive when provoked. It has been associated with CADin a previous study (4).DEPRESSION. Depression was assessed with the 33-itemMMPI-2 Depression content scale (21). It measures variousdepressive symptoms, including dysphoria, lack of motiva-tion, self-depreciation, and suicidal ideations. In a previousstudy that examined several depression measures, this scalewas shown to have the strongest association with CADevents (33).NEGATIVE EMOTION. Negative emotion was measured bythe MMPI Welsh A scale (34). It measures various affectiveand cognitive symptoms of emotional disturbance, such asdysphoric mood, depressive thoughts, and social maladjust-ment. A previous study showed that it was associated withCAD onset over 3 years (9).Health behaviors. Alcohol consumption and cigarettesmoking were obtained by standard questionnaires. Asmoker was defined as smoking ?1 cigarette/day. Accord-ing to earlier research (35), alcohol consumption was di-vided into 3 categories (?0.3, 0.3 to 2, and ?2 drinks perday) to examine a possible curvilinear relationship betweenalcohol and MI. Daily caloric intake was derived from afood frequency survey (36).Blood pressure and anthropometrics. Blood pressure wasmeasured to the nearest 2 mm Hg with a standard mercurysphygmomanometer. Average readings from both armswere obtained. Height was measured to the nearest 0.1 inch,and weight was measured to the nearest 0.5 lb with theparticipant standing in bare feet and undershorts. Bodymass index (BMI) was calculated from height and weight.Blood chemistry assays. Fasting blood samples were as-sayed for glucose and lipid profiles. Values of glucose,high-density lipoprotein cholesterol (HDL-C), low-densitylipoprotein cholesterol (LDL-C), and triglycerides wereobtained by standardized procedures described in earlierstudies (5,6).Diagnosis of MI. Hospital records of all possible MIs werereviewed and confirmed by a board-certified cardiologist.Criteria for MI were consistent with those in the Framing-ham Heart Study (37). Diagnoses were verified by unequiv-ocal electrocardiographic changes (pathologic Q waves) andelevated serum glutamic-oxaloacetic transaminase and lacticdehydrogenase accompanied by chest discomfort. Fatalincidents were confirmed by death certificates indicating MIas the underlying cause.Data analysis plan. Before analysis, non-normal variableswere transformed with a natural log function. Psychologicmeasures were transformed to z scores to facilitate interpre-tation. The relationships between anxiety and participantcharacteristics were examined with Pearson correlations.Cox proportional hazards models were used to estimate therelative risks (RRs) of MI incidence associated with anxietyvariables while controlling for covariates.STANDARD COVARIATES. All proportional hazards modelswere adjusted for a set of standard covariates, including age,education, marital status, fasting glucose, BMI, HDL-C,and systolic blood pressure (SBP).PRIMARY ANALYSES. The primary analyses were conductedto estimate the RRs of MI incidence associated with anxietyvariables, including psychasthenia, social introversion, pho-bia, manifest anxiety, and overall anxiety. For each anxietymeasure, we first estimated its univariate RR and thenassessed its RR adjusted for standard covariates. Further-more, we examined whether clinical elevations (T scores?65) in these anxiety measures constituted significant riskfor MI after adjusting for standard covariates.To reduce the potential number of tests in additionalanalyses, we also attempted to demonstrate that overallanxiety was a representative summary index for all anxietymeasures used in further analyses. by on April 17, 2009 content.onlinejacc.org115JACC Vol. 51, No. 2, 2008January 15, 2008:113–9Shen et al.Anxiety and Myocardial InfarctionDownloaded from

were 11, 16, 19, and 29 MIs in each anxiety group from thelowest to highest quartile (chi-square ? 9.21; degrees offreedom ? 3; p ? 0.05) (Fig. 1), demonstrating that men inhigher anxiety quartiles manifested more incidents.DiscussionThis study demonstrated that anxiety characteristics inde-pendently and prospectively predicted MI incidence over anaverage of 12.4 years among older men after adjusting forsociodemographic background, biomedical variables, healthbehaviors, and even other psychosocial factors. The resultssuggest that moderately elevated anxiety is associated with amodest risk of MI and severe anxiety represents an MI riskthat may warrant clinical attention. The findings indicatethat anxiety not only represents an independent, prospec-tive, and unique risk factor for MI, but may also explain theassociations between MI and other psychosocial risk factorsobserved in earlier studies.Several mechanisms may account for these findings. First,evidence from animal (38), epidemiologic (39), and clinicalstudies (40) suggests that chronic and acute stressors maygive rise to coronary events or predict clinical outcomes (41).It is plausible that highly anxious individuals are more likelyto experience elevated levels of stress repeatedly and chron-ically, thereby exposing them to higher risk for MI. Anumber of pathophysiologic pathways, mostly implicatingexaggerated stress reactivity, have been speculated to explainhow psychosocial factors may confer higher risk for MI.These include dysregulated hypothalamic-pituitary-adrenalaxis and autonomic nervous system, excessive inflammatoryprocess, and disturbed platelet activation (7,42). Although alarger body of evidence has focused on the associationbetween depression and markers of inflammation and co-agulation (43,44), a recent study shows that anxiety isrelated to these markers even after controlling for depression(45). In addition, individuals with anxiety disorders showrelative reductions in cardiac vagal tone and heart ratevariability (46), suggesting that impaired autonomic balancein heart rate regulation may be implicated. Considering therelatively stronger effect of anxiety in predicting MI onset, itwould be important to understand whether anxiety differ-entially promotes these pathogenic mechanisms.Although the present study found that anxiety character-istics were the strongest predictor of MI among psychologicvariables, we would not advocate abandoning assessment ofdepression, hostility, or other related characteristics. Psy-chologic factors are inter-related and may contribute to oneanother in a reciprocal fashion. Recognizing multiple psy-chosocial risk components may better inform risk assess-ment and management for people at higher risk for MI.Furthermore, the anxiety measures assessed more in-grained personality tendencies that are likely to give rise tosituational anxiety symptoms or chronic anxiety disorders.Interestingly, type D personality, comprising social inhibi-tion and negative affectivity, has been associated with poorprognosis of heart disease (14). It appears that interpersonaland social difficulties constitute a major source of distressthat may exacerbate progression of heart disease in eitherinitially healthy population or people with established cor-onary disease.It is worth noting that, consistent with earlier literature(47), being married was a protective factor against CADonset. We speculated that the salutary effect of marriage wasmainly mediated by its association with social support. Thedichotomized marital status, however, is a relatively crudeproxy for social support. More research is needed to scru-tinize how marriage quality may contribute to better car-diovascular health.Several limitations of the study should be considered,which also point to directions for future research. Thesample, consisting of primarily healthy older Caucasianmen, may limit the generalizability of the findings towomen, ethnic minorities, or clinical populations. Further-more, we were not able to examine promising psychophys-iologic mechanisms discussed previously which might ex-plain the observed associations. Future studies addressingthese issues would promote our understanding of the role ofanxiety in the development of heart disease.Reprint requests and correspondence: Dr. Biing-Jiun Shen,Assistant Professor, Department of Psychology, University ofSouthern California, 3620 South McClintock Avenue, Los Ange-les, California 90089-1061. E-mail: bjshen@usc.edu.REFERENCES1. Rozanski A, Blumenthal JA, Kaplan J. Impact of psychological factorson the pathogenesis of cardiovascular disease and implications fortherapy. Circulation 1999;99:2192–217.2. Hemingway H, Marmot M. Evidence based cardiology: psychosocialfactors in the aetiology and prognosis of coronary heart disease.Systematic review of prospective cohort studies. BMJ 1999;318:1460–7. by on April 17, 2009 content.onlinejacc.orgFigure 1 Number of MI Incidents at Different Anxiety LevelsFigure shows number of myocardial infarction (MI) incidents among participantsin each anxiety quartile (chi-square ? 9.21; degrees of freedom ? 3;p ? 0.05).118 Shen et al.Anxiety and Myocardial InfarctionJACC Vol. 51, No. 2, 2008January 15, 2008:113–9Downloaded from

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